DESCRIPTION (adapted from the applicant's description): The objective of this proposal is to study the relationship between cardiac tissue structure and the electrical events in the process of defibrillation. Defibrillation current traverses the myocardium along convoluted intracellular and extracellular pathways channeled by the tissue structure. It distributes across cell membranes, thus, inducing change in transmembrane potential throughout the myocardium. It is postulated that in the process of defibrillation, the dominant shock-induced transmembrane potential change in the tissue arises from its macroscopic fibrous organization. In particular, changes in the fiber orientation in space, as well as non-uniformity of the extracellular electric field along fibers, are responsible for large-scale transmembrane potential change in the tissue bulk. These spatially distributed regions of induced membrane depolarization and hyperpolarization affect pre-existing reentrant activations in the fibrillating myocardium . More specifically, graded responses and new activations arise in regions of depolarization at the make of the shock. They combine with excitations emanating from regions of hyperpolarization at the break of the shock to ultimately result in either prevention of further wavefront propagation or, for weak shocks, reinitiation of fibrillation. To test these hypotheses, computer simulations will be carried out in (1) anatomically based rabbit ventricular geometry and fiber architecture, (2) accurate description of myocardial ionic current dynamics under strong electric fields, (3) representation of membrane electroporation, and (4) adequate protocols for the generation of reentrant activation patterns. The specific aims are to: (i) analyze rigorously the relationship between myocardial fibrous organization and shock-induced transmembrane potential changes, and (ii) characterize the interaction between shock-induced potential change and inherent refractoriness of the fibrillating myocardium. Experimental measurements are proposed to validate the defibrillation model expected to guide experimental design and interpretation of experimental findings related to electrical defibrillation of the heart.